Title:
MULTIMERIC TETHERED LIGANDS AND THEIR USE IN RECEPTOR-LIGAND INTERACTIONS
Document Type and Number:
WIPO Patent Application WO1999025384
Kind Code:
A3
Abstract:
Multimeric tethered ligands are disclosed, comprising a plurality of ligand moieties tethered to a joint moiety, wherein each ligand moiety comprises a ligand for at least one receptor protein having multiple binding sites for the ligand and each ligand moiety is linked by a tether moiety to that joint moiety. Exemplary dimeric tethered ligands are disclosed in which the tether is a simple polymer, polyethylene glycol, which are therefore called "polymer-linked dimers" (PLDs). Exemplary PLDs containing two guanosine 3', 5' cyclic monophosphate (cGMP) moieties are described which are up to 1,000-fold more potent than cGMP in activating cyclic nucleotide-gated (CNG) channels and protein kinases. Each protein responds optimally to a PLD with a different average polymer length, indicating that each has a unique spacing of binding sites. Since optimal ligands are selected empirically, the multivalent tethered ligand strategy allows identification of highly potent and specific agents with no prior structural information about target proteins.
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Inventors:
KRAMER RICHARD H
KARPEN JEFFREY W
KARPEN JEFFREY W
Application Number:
PCT/US1998/024467
Publication Date:
July 29, 1999
Filing Date:
November 16, 1998
Export Citation:
Assignee:
UNIV MIAMI (US)
UNIV TECHNOLOGY CORP (US)
UNIV TECHNOLOGY CORP (US)
International Classes:
A61K47/48; (IPC1-7): A61K47/48
Domestic Patent References:
| WO1996040772A2 | 1996-12-19 | |||
| WO1998003632A1 | 1998-01-29 |
Other References:
KRAMER R H ET AL: "Spanning binding sites on allosteric proteins with polymer-linked ligand dimers.", NATURE, (1998 OCT 15) 395 (6703) 710-3. JOURNAL CODE: NSC. ISSN: 0028-0836., ENGLAND: United Kingdom, XP002103102
KRAMER, R. H. (1) ET AL: "Spanning binding sites on cyclic nucleotide-gated channels and kinases with polymer-linked ligand dimers.", BIOPHYSICAL JOURNAL, (FEB., 1998) VOL. 74, NO. 2 PART 2, PP. A125. MEETING INFO.: FORTY-SECOND ANNUAL MEETING OF THE BIOPHYSICAL SOCIETY KANSAS CITY, MISSOURI, USA FEBRUARY 22-26, 1998 ISSN: 0006-3495., XP002103103
SCHUCKER SUZANNE B.: "Discovering High Afinity Ligands for Proteins: SAR by NMR", SCIENCE, vol. 274, 1996, pages 1531 - 1534, XP002103104
HUBER M ET AL: "2,2'- Dithiobis (N-ethyl- spermine -5-carboxamide) is a high affinity, membrane-impermeant antagonist of the mammalian polyamine transport system.", JOURNAL OF BIOLOGICAL CHEMISTRY, (1996 NOV 1) 271 (44) 27556-63. JOURNAL CODE: HIV. ISSN: 0021-9258., United States, XP002103105
MATHAI MAMMEN ET AL.: "Polyvalent Interactions in Biological Systems: Impications for Design and Use of Multivalent LIgands and Inhibitors", ANGEW. CHEM. INT. ED., vol. 37, 1998, pages 2754 - 2794, XP002103106
LEBOULLUEC, KAREN L. ET AL: "Bivalent indoles exhibiting serotonergic binding affinity", BIOORG. MED. CHEM. LETT. (1995), 5(2), 123-6 CODEN: BMCLE8;ISSN: 0960-894X, 1995, XP002103840
HAHN E F ET AL: "Irreversible opiate agonists and antagonists. II. Evidence against a bivalent mechanism of action for opiate azines and diacylhydrazones.", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, (1985 DEC) 235 (3) 839-45. JOURNAL CODE: JP3. ISSN: 0022-3565., United States, XP002103841
KRAMER, R. H. (1) ET AL: "Spanning binding sites on cyclic nucleotide-gated channels and kinases with polymer-linked ligand dimers.", BIOPHYSICAL JOURNAL, (FEB., 1998) VOL. 74, NO. 2 PART 2, PP. A125. MEETING INFO.: FORTY-SECOND ANNUAL MEETING OF THE BIOPHYSICAL SOCIETY KANSAS CITY, MISSOURI, USA FEBRUARY 22-26, 1998 ISSN: 0006-3495., XP002103103
SCHUCKER SUZANNE B.: "Discovering High Afinity Ligands for Proteins: SAR by NMR", SCIENCE, vol. 274, 1996, pages 1531 - 1534, XP002103104
HUBER M ET AL: "2,2'- Dithiobis (N-ethyl- spermine -5-carboxamide) is a high affinity, membrane-impermeant antagonist of the mammalian polyamine transport system.", JOURNAL OF BIOLOGICAL CHEMISTRY, (1996 NOV 1) 271 (44) 27556-63. JOURNAL CODE: HIV. ISSN: 0021-9258., United States, XP002103105
MATHAI MAMMEN ET AL.: "Polyvalent Interactions in Biological Systems: Impications for Design and Use of Multivalent LIgands and Inhibitors", ANGEW. CHEM. INT. ED., vol. 37, 1998, pages 2754 - 2794, XP002103106
LEBOULLUEC, KAREN L. ET AL: "Bivalent indoles exhibiting serotonergic binding affinity", BIOORG. MED. CHEM. LETT. (1995), 5(2), 123-6 CODEN: BMCLE8;ISSN: 0960-894X, 1995, XP002103840
HAHN E F ET AL: "Irreversible opiate agonists and antagonists. II. Evidence against a bivalent mechanism of action for opiate azines and diacylhydrazones.", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, (1985 DEC) 235 (3) 839-45. JOURNAL CODE: JP3. ISSN: 0022-3565., United States, XP002103841
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